Camptothecin is a cytotoxic alkaloid first isolated by Wall and his coworkers (J. Am. Chem. Soc. 88 3888, 1966) from leaves and barks of Camptotheca accuminata (NYSSACEAE), a plant native to China. This alkaloid has a pentacyclic structure consisting of a fused ring system of quinoline rings (rings A and B), a pyrrolidine ring (ring C), an alpha-pyridone ring (ring D), and a six-membered lactone ring (ring E). The compound displays dextro-rotation due to the S-configuration of a tertiary hydroxy group in the 20-position. Earlier reports on the carcinostatic activity of camptothecin were based on inhibitor activity toward an experimentally transplanted carcinoma such as leukemia L-1210 in mice, or Walker 256 tumor in rats (Chem. Rev. 23 (1973), 385; Cancer Treat. Rep., 60 (1967), 1007] stimulated synthetical researches on camptothecin, but the subsequent biological evaluation in the reports indicated that this compound is highly toxic and consequently is unusable as a chemotherapeutic agent. Hemorrhagic enterocolitis was the major dose-limiting toxic effect of the drug in preclinical studies in the beagle and rhesus monkey. Minimal hepatotoxicity and moderate eosinophilia and bone marrow depression were also noted.
Camptothecin is practically insoluble in aqueous vehicles that are suitable for parenteral administration. Therefore, it becomes necessary to modify the chemical structure of the alkaloid to make it water soluble. Sodium camptothecin (Formula 2), obtained by opening the lactone ring of the parent compound with sodium hydroxide, has excellent solubility properties, (&gt;50 mg/ml in water), and therefore received much of the attention in the preclinical and clinical stages. However, as reported in Gottlieb et al., Cancer Chemother. Rep. 54, 461 (1970), Moertel et al., ibid, 56, 95 (1972); Gottlieb et al., ibid, 56, 103 (1972), the early clinical studies with this agent were disappointing. The sodium salt displayed unexpected toxicity that precluded achievement of therapeutically useful doses. ##STR2##
Despite these clinical setbacks, interest in camptothecin as an anti-tumor agent has remained very high. Careful evaluation of these agents in animal models revealed that the sodium salt is only 10-20% as potent as the parent camptothecin [Wani et al., J. Med. Chem. 23, 554 (1980)]. In addition, important parameters for anti-tumor activity in the camptothecin series have been established [Wall et al., Ann. Rev. Pharmacol. Toxicol. 17, 117 (1977)]. These studies revealed that the intact lactone ring, ring E, and hydroxyl group at position 20 are essential for antitumor activity.
Clearly, there is a need to obtain camptothecin in a water-soluble form while retaining the structural elements (i.e., 20-hydroxyl and ring E lactone) that are essential for its pharmacological activity.
A number of attempts have heretofore been made to provide more active derivatives of camptothecin, but none of these compounds has been disclosed to be more water soluble than the parent drug.
Miyasaka et al., U.S. Pat. No. 4,399,282, disclose camptothecin derivatives which are said to have either high anti-tumor activity or low toxicity, wherein the 7-hydroxymethyl group is converted into a 7-alkoxymethyl group or a 7-acyloxymethyl group with or without simultaneous acylation of the 20-hydroxyl group. There is no disclosure that acylation of the 20-hydroxyl group provides camptothecin derivatives which are water-soluble. Winterfeldt et al., U.S. Pat. No. 3,894,029, disclose compounds of the formula: ##STR3##
wherein R.sup.2 is ethyl. There is no disclosure that this ethyl group in the 20-position increases the water solubility of the compound.
Japanese Pat. No. 57-116074 discloses camptothecins of the following formula: ##STR4##
wherein R.sup.3 is lower alkyl or acyl. These compounds are said to be less toxic and more active against leukemia L-1210 in mice. However, there is no indication that these compounds are more soluble in water.